Bird flu viruses — mutations to watch out for

They can become capable of infecting cells along the human upper airway with a few mutations to a key protein on their surface

Bird flu viruses H5N1 and H7N9 that have sporadically infected humans, could, with a few mutations to a key protein on their surface, become capable of infecting cells along the human upper airway and thereby take a step towards turning into pandemic-causing strains, according to research that has just been published in the scientific journal Cell.

People have typically caught these viruses from infected poultry, and there has been little evidence of person-to-person transmission. However, both have caused a more severe disease among infected individuals, with a higher fatality rate, than human-adapted flu viruses. With lack of any pre-existing immunity to the two viruses, experts are concerned that if either gains the ability to pass readily from human to human, it can set off a dangerous flu pandemic.

Flu viruses, which spread easily among humans, do so through fine droplets that spew out when infected individuals cough or sneeze. To become similarly transmissible, a bird flu virus must be able to enter and infect cells in the upper respiratory tract. The first step in that entry process is for a viral surface protein, haemagglutinin (HA), to bind strongly to a receptor molecule found on cells lining the human airway. For that, bird flu viruses need changes to their HA that switches its binding from avian to human receptors.

A team led by Ram Sasisekharan, professor at the Massachusetts Institute of Technology, modelled the key structural features that the HA of H5N1 and H7N9 viruses need to bind well to human receptors. Some of the recent H5 HAs required as few as one or two amino acid mutations to switch to human receptors, the scientists reported in one of two papers being published in Cell.

In research that was published last year, two groups — one led by Yoshihiro Kawaoka in the U.S. and the other by Ron Fouchier in the Netherlands — examined what changes to important viral proteins would make H5N1 easily transmissible among ferrets, an animal model for what happens in humans. However, Professor Sasisekharan and his colleagues found that introducing those amino acid changes into the HA of current strains of H5N1 would not improve their binding to human receptors. “It is the network of amino acids in the HA and how they interact with the receptors that become key in the switch from avian to human receptors,” he said in an e-mail.

In the second Cell paper, the team noted that the H7N9 bird flu virus currently bound poorly to human receptors. However, “should a single amino acid mutation occur, this would result in structural changes within the receptor binding site that allow for extensive binding to human receptors present in the upper respiratory tract.”

“Our findings can be put to use to monitor the evolution of H5N1 and H7N9 viruses in the field as well as in the clinic if and when there is an outbreak,” said Professor Sasisekharan in a press release.

Vincent Racaniello, professor of virology at Columbia University, said in an e-mail: “This work is important because it defines structural features in the receptor binding site of H5 HA that are critical for switching from avian to human receptor binding. In an e-mail, he said: “However, switching of H5 HA to human receptor specificity is not sufficient to gain human-to-human transmissibility; what other changes are needed, in which genes and how many is anyone’s guess.”

In the case of the H7N9 virus, the study had shown that its HA might be only one amino acid change away from higher binding to human receptors. “However, it does not follow that such a virus would be able to transmit by aerosol among humans, a property which the H7N9 viruses infecting humans currently do not possess,” Professor Racaniello said.